Bone and joint disorders caused by autoimmune disease characterized by chronic inflammation and bone destruction because of an abnormal increase in bone resorption by osteoclasts are very common. The most common joint disease is osteoarthritis (OA), it can cause constant pain, suffering, reduced limb function, loss of mobility, and loss of quality of life for 27 million Americans. Americans have a 46% and 25% lifetime risk of developing OA in their knee and hip. One third of older age American women suffer from OA, which is a progressive loss of bone mineral which increases their risk of bone fracture. Trauma, radiation, joint replacements, hip replacements, dental implants, and some drugs can cause osteonecrosis (ON), where areas of bone have died. Unfortunately, despite the high degree of disability and suffering caused to millions of people, there is no cure for OA, osteoporosis (OP), or ON, except to surgically remove the immobile joint and to replace it with an implant. The FDA has approved the use of bone antiresorptive medications to slow the rate of bone loss and anabolics to increase the rate of bone formation, but these have a limited effectiveness and cannot cure OA, OP, or ON. Although bone and joint disorders are more common in middle-age and elderly people, it is not accurate to claim that the joints and bone have “worn out”. This is because in healthy individuals, the deposition of bone by osteoblasts is matched by the resorption of bone by osteoclasts. However, when there is an abnormal increase in bone resorption the osteoclasts have become more active and resorbed bone and surrounding soft tissues. Some other immune cell types, such macrophages, and T or B lymphocytes have been reported to be involved in the pathogenesis of chronic inflammation in RA. However, bone destruction is considered to be mainly controlled by enhanced activation of osteoclasts, the only somatic cell type capable of resorbing bone matrices. Therefore, the inventors of the present invention believe the key to preventing the bone resorbing processes of OA, OP, and ON is to block the activity of the osteoclasts.
An osteoclast is a cell which resorbs bone. Osteoclasts are about 150-200 μm in diameter, typically have five nuclei, and a cytoplasm filled with acid phosphatase which can be released to resorb bone. Normal bone homeostasis, bone formation and bone resorption are closely coupled processes involved in the normal remodeling of bone. In OP, the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass without a defect in bone mineralization. In post-menopausal women, osteoclast activity may increase because of a decrease in circulating estrogen after the menopause. Osteoclast activity may also increase in men who suffer a decrease in circulating testosterone. These physiological changes can result in a net loss of bone. The amount of bone available for mechanical support of the skeleton eventually falls below the fracture threshold and a bone fracture can occur with little or no trauma. Osteoclasts can also resorb bone at sites of trauma, implants, materials, infection, and surgery. The osteoblast resorption of bone is a self-perpetuating process, which can only be halted by the surgical removal of the resorbed and adjacent tissues, as well as any materials or implants, traumatized tissues, or infection, which stimulated the osteoclasts. The current inventors therefore believe the ability to halt the bone resorbing activity of the osteoclasts could be beneficial to prevent bone loss, and the disabling and dysfunctional effects it can have on patients.
Particularly devastating is the occurrence of bone resorption by osteoclasts at the site of bone defect repair. Ideally, these inventors believe what is needed is an implantable osteogenic scaffold which can control the osteoblasts, osteoclasts and local inflammatory cells within the site of a bone defect to accomplish its regeneration.
A few inhibitors of collagen degradation have been identified in various cell lines, type 1 collagen is the major organic component of bone. The present inventors found some potential inhibitors of the osteoblast degradation of bone and collagen are; hydroxamate-based matrix metalloproteinase (MMP) inhibitors, thiol-based MMP inhibitors, Pyrimidine-based inhibitors, hydroxypyrone-based MMP inhibitors, phosphorus-based MMP inhibitors, tetracycline-based MMP inhibitors, and endogenous MMP inhibitors also known as tissue inhibitors of metalloproteinases (TIMPs). The names of some of these Galardin, Decorin, Actinonin, Marimastat, Batimastat, Ilomastat, Interleukin-1, oncostatin M, Tanomastat, Cipemastat, Rebimastat, phosphodiesterase type 4 (PDE4) inhibitor, hydroxamate-based MMP inhibitors, MMI-270, MMI-166, ABT-770, RS-130830, compound 239796-97-5, compound 420121-84, compound 544678-85, Compound 556052-30-3, Ro 282653, compound 848773-43-3, compound 3-hydroxypyran-4-one also called 868368-30, metastat (also known as COL-3), Prinomastat, and Gelatinases.
One third of older age American women suffer from OP, which is a progressive loss of bone mineral which increases their risk of bone fracture. After women reach the menopause, there is a sudden drop in their levels of estrogen. The lack of estrogen is a major causal factor of OP, because it causes an increase in the osteoclast degradation of bone, resulting in impaired bone mass and architecture. The U.S. Food and Drug Administration has approved estrogen with progesterone hormone therapy (HT) for post-menopausal women to increase their bone mineral density and to reduce their risk of an OP-related bone fracture. Because of the potential effects of hormones and growth factors on the osteoclast degradation of bone, these inventors believe there is a need to investigate the molecular mechanisms of how estrogen (estradiol), testosterone, progesterone, Gonadotropin-releasing hormone (GnRH), insulin, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Sphingosine-1-phosphate (S1P), Bone morphogenetic proteins 2 and 4 (BMP-2), (BMP-4), Transforming growth factor beta 1 (TGF-β1) can alter the proliferation of osteoclasts, as well as their bone and collagen degradation.
A bone defect can be caused by trauma, tumor, cancer, radiation, drugs, infection, implant surgery, chronic inflammation, or a disease, such as osteoarthritis, osteoporosis, and osteonecrosis. In healthy individuals, the deposition of bone by osteoblasts is matched by the resorption of bone by osteoclasts as reported by Bocanegra-Pérez M S et al in an article entitled, “Bone metabolism and clinical study of 44 patients with bisphosphonate-related osteonecrosis of the jaws” in the Med Oral Patol Oral Cir Bucal. 2012; 17:e948-55. However, when there is an abnormal increase in bone resorption the osteoclasts have become more active and resorb bone and surrounding soft tissues reported by Crotti T N et al in an article entitled, “Factors regulating osteoclast formation in human tissues adjacent to peri-implant bone loss: expression of receptor activator NFkappaB, RANK ligand and osteoprotegerin” in Biomaterials. 2004; 25:565-73.
Osteoclasts are bone-resorbing giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors as shown by in vivo fluorescence imaging of bone-resorbing osteoclasts. Upon stimulation by cytokines, such as M-CSF and RANK ligand, osteoclast precursor monocytes migrate and attach onto the bone surface. They then fuse with each other to form giant cells (differentiation) and mediate bone resorption.